Title: Testing and forecasting hippocampal theta wave propagation in learning and memory Abstract: Psychiatric disease states are associated with profound deficits in cognition that can severely compromise one's ability to live independently. In order to understand and effectively treat mental health disorders, it is necessary to determine how the information that supports adaptive behaviors is relayed across large networks of neurons. Brain rhythms, such as local field potential oscillations, have been hypothesized to organize neural circuit processing on multiple timescales in order to coordinate thought and action. Moreover, abnormalities in brain rhythms have been observed in humans afflicted with schizophrenia, autism, bipolar disorder, and a wide array of other neurological diseases. Among the neural oscillations affected by psychiatric diseases is the hippocampal theta rhythm, which is critical for learning and memory and is disrupted in schizophrenia and anxiety disorders. Importantly, the theta oscillation has been found to propagate along the hippocampal dorsoventral axis. Although the propagating theta wave has never been explicitly examined in the context of a cognitive task, this traveling brain rhythm could serve the fundamental purpose of integrating information across the hippocampus in support of learning and memory. The long-term goal of this research is to determine how neurons act in concert to guide behavior and to develop novel therapeutic strategies for normalizing brain rhythms in disease. The primary objective of the current proposal, which is the first step toward attaining our long-term goal, is to determine the behavioral and cellular mechanisms that modulate wave propagation, and to forecast oscillatory activity across brain regions. We will attain this by testing the central hypothesis that the propagation of the theta oscillation, coordinated via septal and entorhinal influences, can be described as a weakly nonlinear wave, altering its dynamics as a function of learning and memory with the following specific aims: 1) Determine the influence of cognition and septal input on hippocampal theta wave propagation, 2) Determine the influence of medial entorhinal input on hippocampal theta wave propagation, and 3) Develop a nonlinear algorithm to forecast theta wave propagation. The rationale is that this approach will uncover fundamental principles of wave propagation that will enable new insight into neuronal coordination in the normal brain and mechanisms of dysfunction in neuropsychiatric illness. This proposal is innovative because we will integrate cross-disciplinary theoretical and empirical approaches to develop an integrated understanding of large-scale neuronal dynamics. The significance of this contribution is an unprecedented understanding of activity propagation in the hippocampus during learning and memory that will provide insights into the temporal coordination of information, developing the critical foundation for understanding how cognition is disrupted in psychiatric disease.